Regulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

doi:10.1073/pnas.0601335103

Regulatory CD56^bright natural killer cells mediate immunomodulatory effects of IL-2Rα-targeted therapy (daclizumab) in multiple sclerosis

*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
^†Department of Neurology, University of Cincinnati, Cincinnati, OH 45230;
^§Experimental Immunology Branch and
^{^‖}Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
^††Catalan Institute for Research and Advanced Studies and Unidad de Neuroimmunologia Clinica, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain

Contributed by Thomas A. Waldmann, February 16, 2006
↵ ^¶M. Catalfamo and S.R.-S. contributed equally to this work.

Abstract

Administration of daclizumab, a humanized mAb directed against the IL-2Rα chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4⁺ T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4⁺ and CD8⁺ T cells and significant expansion of CD56^bright natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56^bright NK cells and contraction of CD4⁺ and CD8⁺ T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56^bright NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.

Footnotes

^‡To whom correspondence may be addressed at:
Department of Neurology, University of Cincinnati, 231 Albert Sabin Way, Medical Science Building Room 4458, Cincinnati, OH 45267-0525.
E-mail: bibi.bielekova{at}uc.edu
**To whom correspondence may be addressed. E-mail: tawald{at}helix.nih.gov
Author contributions: B.B., T.A.W., H.M., P.A.H., and R.M. designed research; B.B., M. Catalfamo, S.R.-S., A.P., and M. Cerna performed research; B.B. and M. Catalfamo analyzed data; and B.B., M. Catalfamo, T.A.W., H.M., P.A.H., and R.M. wrote the paper.
Conflict of interest statement: B.B., T.A.W., H.M., and R.M. are coinventors on National Institutes of Health-owned patents related to the use of daclizumab in multiple sclerosis and as such are receiving royalty payments.
Abbreviations:

Abbreviations:

MS,

multiple sclerosis;

PBMC,

peripheral blood mononuclear cell;

NK,

natural killer;

TW,

transwell;

CFSE,

5-(and 6)-carboxyfluorescein diacetate succinimidyl ester.